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A chemical degradation scheme is reported, which permits the measurement of the radioactivity of each carbon atom of nicotinic acid. Nicotinic acid is decarboxylated by heating with copper chromite to give carbon dioxide (C-7) and pyridine. The pyridine is converted into 4-nitropyridine 1-oxide, which is heated with aqueous calcium hypobromite to give tribromonitromethane. Combustion of the latter gives carbon dioxide derived from C-4 of the nicotinic acid. Nicotinic acid is also reduced to nipecotic acid, which is oxidized to succinic acid by acidic potassium permanganate. Stepwise degradation of the succinic acid by standard procedures gives two samples of carbon dioxide, which correspond to C-3, C-6 and C-4, C-5 of the nicotinic acid. Benzoylation of the nipecotic acid, followed by oxidation with permanganate at pH7, gives 5-amino-4-carboxyvaleric acid; this is converted into 2-methyleneglutaric acid by the action of nitrous acid. Hydrogenation of the 2-methyleneglutaric acid over rhodium in methanol gives 2-methylglutaric acid, which is oxidized with dilute chromic acid to acetic acid. Stepwise degradation of the acetic acid by standard procedures gives two samples of carbon dioxide, which correspond to C-2 and C-3 of the nicotinic acid. Thus the radioactivities of C-2, C-3, C-4 and C-7 are determined directly and those of C-5 and C-6 by difference. The method was shown to be isotopically valid for [2,3,7-(14)C]-, [4,6-(14)C(2)]- and [5-(14)C]-nicotinic acid.
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Nicotinic acid (niacin) has been used clinically to manage dyslipidemia for many years. The molecular target of nicotinic acid was unknown until the recent revelation of human G-coupled receptor HM74a as the high affinity receptor for nicotinic acid. In searching for a cell line expressing endogenous human HM74a receptor, we have identified that the A431 cell line, a human epidermoid cell line, expresses a high level of HM74a receptor. An HM74a-specific real time PCR probe set was designed and the mRNA levels of HM74a in A431 and 32 other cultured cell lines were measured quantitatively. When the mRNA expression of HM74a in A431 cells was compared to that in human primary preadipocytes, adipocytes and adipose tissue, we found that the level in A431 was about 10- fold higher than that in adipocytes and adipose tissue. The ratio of HM74a:HM74 mRNA was measured quantitatively and it was determined to be 3:2 in A431 cells. The function of the HM74a receptor in A431 cells was evaluated for its ability to inhibit forskolin-induced cAMP production. Pertussis toxin treatment abolished the inhibition. Our data suggest that the A431 cell line may serve as a cellular model for further investigation of niacin/HM74a-mediated signal transduction in modulating metabolism. A431 cell line may also provide a valuable cell model to study prostaglandin production upon HM74a activation to improve our understanding of niacin/HM74a-mediated skin flushing.
HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A(2) (PLA(2))/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca(2+)-mobilization and enhanced bradykinin-promoted Ca(2+)-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPARgamma agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.
The effects of leucine and alpha-ketoisocaproic acid on the NAD biosynthesis from (carboxyl-14C) nicotinic acid or (benzene ring-U-14C) tryptophan were investigated in the isolated rat liver cells. The quantities of NAD formed from tryptophan and nicotinic acid increased linearly during 60 min-incubation. Leucine, which was essentially not metabolized by the isolated liver cells, had no inhibitory effect on the NAD synthesis. On the other hand, alpha-ketoisocaproic acid, alpha-keto acid analogue of leucine, which was rapidly metabolized to ketone bodies, diminished a quantity and a specific radioactivity of NAD synthesized from both tryptophan and nicotinic acid to a similar extent. Palmitic acid, which was oxidized to ketone bodies by the isolated rat liver cells, also diminished an amount and a specific radioactivity of NAD synthesized from nicotinic acid. Ketone bodies exogenously added to the incubation medium exerted a similar inhibitory effect on NAD synthesis. Results demonstrate that substances which can be oxidized to ketone bodies are inhibitory to NAD biosynthesis from tryptophan and nicotinic acid in the isolated rat liver cells.
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Nicotinic acid concentrations in the serum over 80 mug/100 ml induce at the start of high dosage nicotinic acid therapy an acute rise in bilirubin to 1-3mg/100 ml serum. Even after postprandial administration there are clearly raised bilirubin concentrations in the serum. After treatment for 1 week with 0.5 g nicotinic acid daily by mouth the bilirubin increase is no longer detectable. The increased bilirubin concentrations in the serum are apparently the result of a transient inhibition of glucuronyl-transferase and is not a symptom of an acute liver disorder. When starting high dosage nicotinic acid therapy, therefore, disorders of the bilirubin metabolism and liver function must be excluded by differential diagnosis in doubtful cases. Further investigations are necessary to see whether the high concentrations of nicotinic acid in the serum cause competition with other drugs for the bilirubin-specific glucuronyl-transferase.
BACKGROUND: Nicotinic acid, widely used to lower serum cholesterol levels, may rarely cause cholestatic jaundice. SUMMARY: A 61-year-old white man with hypercholesterolemia complained of marked pruritus and became jaundiced after taking 3.0 g of crystalline nicotinic acid daily for 13 months. His total serum bilirubin level was increased at 144 mumol/L (8.4 mg/dL) and his alkaline phosphatase level was markedly elevated at 35.00 mukat/L (2100 U/L). Endoscopic retrograde cholangiopancreatography failed to demonstrate an obstructive lesion in the extrahepatic biliary system, computed tomography showed no intrahepatic dilatation, and ultrasonographic studies of the liver, gallbladder, and pancreas were normal; these factors all suggest intrahepatic cholestasis. Symptoms improved and liver function test results returned to normal within 51 days after stopping the drug. CONCLUSIONS: Nicotinic acid-induced cholestatic jaundice may not be as rare as previously thought, and physicians should observe their patients for it.
1. Nicotinic acid-deficient rats were given a dose of niacytin or an equivalent one of free nicotinic acid or hydrolysed niacytin. 2. The excretion of N'-methylnicotinamide and of tertiary nicotinoyl derivatives in urine showed that niacytin was not metabolized as free nicotinic acid, although hydrolysed niacytin was equivalent to free nicotinic acid. 3. Little or none of the niacytin dose was recovered as tertiary nicotinoyl derivatives in faeces. This result was not affected by fitting rats with tail-cups to prevent coprophagy. 4. At the high doses used niacytin restored the growth rate of the deficient animals because of a small degree of hydrolysis of the bound nicotinic acid.
We have deleted the yeast gene YJR025c and shown that this leads to an auxotrophy for nicotinic acid. The deduced protein sequence of the gene product is homologous to the human 3-hydroxyanthranilic acid dioxygenase (EC 1.13.11.6) which is part of the kynurenine pathway for the degradation of tryptophan and the biosynthesis of nicotinic acid. In cell-free extracts the 3-hydroxyanthranilic acid dioxygenase activity is proportional to the copy number of the YJR025c gene. As YJR025c encodes the yeast 3-hydroxyanthranilic acid dioxygenase, we have named this gene BNA1 for biosynthesis of nicotinic acid.
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